Development of artificial lymph node for in situ immunomodulation (NanoLymph)

Cellular therapies aim to treat or manage disease by introducing living cells that integrate into the host and restore or eliminate dysfunctional tissues. Despite their clinical success, the host immune response to cellular treatments remains a challenge since traditional approaches for controlling immune rejection involve systemic immunosuppression, which results in severe off-target toxicity. One alternate strategy for restraining immune responses involves harnessing the natural immunomodulatory capabilities of Regulatory T-cells (Tregs), a specialized subset of T cells that suppress inflammatory immune responses and can promote induction and maintenance of transplantation tolerance. To achieve long-term immunological tolerance with fewer systemic side effects, we propose using the NanoLymph platform, a 3D-printed implantable subcutaneous device for continuous localized recruitment of Tregs. This device features a dual-reservoir system for the sustained release of immunomodulatory agents through a nanoporous membrane and a vascularized compartment that supports cell homing and allograft integration with the host. The current work presents the development and characterization of lymphatic and vascular growth within the NanoLymph upon implantation. We also show sustained, continuous elution of immunomodulatory agents, both in vitro and in vivo. In summary, we demonstrate NanoLymph platform’s capacity for sustained released of immunomodulatory agents to produce a safe and localized immunosuppressive environment that is clinically relevant in transplant operations.